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July 2, 2012

New Target In Ewing’s Sarcoma

by editor

Ewing´s sarcoma is a bone cancer commonly diagnosed in about 250 U.S. teenagers per year. If early chemotherapy is effective, improvement can be durable. But for children and teens who respond poorly to a first attempt at chemotherapy or if the disease spreads, long-term survival can be less than 10 percent.

A University of Colorado Cancer Center study published this week in the journal Molecular Cancer Research shows an important difference that may explain why some respond and some don´t: the existence of high levels of the protein EYA3.

“First, levels of EYA3 could be a tool in offering an accurate prognosis and choosing how aggressively to treat Ewing´s Sarcoma, and second we hope that by lowering levels of EYA3, we could help increase the effectiveness of existing therapies for Ewing´s sarcoma,” says Tyler Robin, PhD, first author of the recent paper.

Researchers recently defined the role of EYA3 as a DNA repair molecule and Tyler showed that EYA3 has a similar repair role in Ewing´s sarcoma — high levels of EYA3 help the tissue survive during and recover after treatment with chemotherapy. Importantly, when Robin knocked down EYA3 in Ewing´s sarcoma cells, they became sensitized to chemotherapy.

“The genetic mutation that creates Ewing´s sarcoma also leads to high levels of EYA3,” says Heide Ford, PhD, investigator at the CU Cancer Center and associate professor in the CU School of Medicine department of ob/gyn, and the paper´s senior author.

The mutation Ford refers to and that creates Ewing´s sarcoma is the fusion of a gene from chromosome 22 to a gene in chromosome 11. Known as a EWS/FLI translocation, this mutation turns off a cell´s ability to make another, intermediate step known as miR-708 — a molecule that helps to decide what parts of the genome do and don´t get read and manufactured into proteins. In healthy tissue, miR-708 turns off the production of EYA3; in Ewing´s sarcoma, miR-708 is down and so EYA3 is up.

“Our next step is to test small molecule inhibitors against EYA3 to determine which inhibitors best sensitize Ewing´s sarcomas to chemotherapy,” says Ford.

Robin and Ford hope that recognizing EYA3 levels, reducing these levels directly, or intervening in the steps that lead to its over-production will help predict outcomes, make decisions about existing treatments, and eventually lead to new treatments for Ewing´s sarcoma.